Many abused drugs are also powerful analgesics. A thorough understanding of the neural mechanisms underlying opioid analgesia should lead to more effective pain treatment and concurrent reduction in the non-therapeutic effects. The monoamines 5-hydroxytryptamine (5-HT) and norepinephrine (NE) have been implicated in the mediation of opioid analgesia. Recently, multiple opioid analgesic systems have been characterized on pharmacological and neuranatomical bases. The proposed series of experiments will investigate the role of 5-HT and NE in analgesia mediated by mu1, mu2, delta1, delta2, kappa1, and kappa3 opioid receptors. Mice will be injected with selected agonists for each of these receptor subtypes, and tested for tail-flick and hot-plate analgesia. Mice pretreated with selective reuptake blockers to increase the levels of 5-HT or NE in the synapse have been tested for potentiation of analgesia produced through each of the opioid mechanisms. Neurotoxic lesion of 5-HT and NE neurons may produce differential attenuation of analgesia. Cross-tolerance between the analgesia produced by 5-HT and alpha receptor agonists and mu1, mu2, delta1, delta2, kappa1 and kappa3 analgesia will be assessed. To enable a more detailed neuranatomical investigation, multiple opioid analgesic mechanisms will be characterized in rats using selective opioid agonists and antagonist and local microinjections. Subsequently, the analgesia produced by microinjections of selective opioid agonists into brain areas associated with analgesia will be characterized using neurotoxins. Although other groups have examined the role of monoamines in opioid analgesia, this series of experiments differs in that they will distinguish between analgesia produced by stimulation of mu1, mu2, delta1, delta2, kappa1 and kappa3 opioid receptors, and will examine the interaction of 5-HT and NE with respect to each of these receptor subtypes. In this way, we expect to clarify previous controversial and conflicting data, and gain new insights into the neural mechanisms of opioid analgesia. This may lead to more judicious and efficacious analgesic therapies.